Aryl-substituted piperazinyl-alkylamino-uracils, -uracil ethers and -uracil thioethers and method for their production

ABSTRACT

Aryl-substituted piperazinyl-alkylamino-uracils, the corresponding uracil ethers and uracil-thioethers and their pharmaceutically acceptable salts such as the hydrochloride, and method for the preparation of these compounds. The novel compounds are useful for lowering the blood pressure in mammalians.

This invention concerns new aryl-substitutepiperazinyl-alkylamino-uracils and the uracil ethers and uracilthioethers corresponding to the general Formula I and their salts withpharmaceutically acceptable acids. ##SPC1##

In this and succeeding formulas R¹ and R² each represent hydrogen, alinear or branched, lower alkyl group having up to 6 carbon atoms, or acycloalkyl or phenyl group;

R³ represents hydrogen, a linear or branched, alkyl, aralkyl, aryl orcycloalkyl group having up to 12, preferably 6 carbon atoms, a halogenatom or a nitro, nitroso, amino, alkylamino, dialkylamino, acylamino,acyl, formyl, ethoxy carbonylamino group, or the thiocyanato group, the--CONHR⁴ group, wherein R⁴ is an alkyl group having up to 4 carbon atomsor a phenyl or a substituted phenyl like alkyl-substituted (e.g. loweralkyl up to 4 carbon atoms);

X represents the --NR⁵ -- group, wherein R⁵ is a hydrogen atom or alinear or branched alkyl group having up to 4 carbon atoms or an oxygenor sulfur atom;

A represents a linear or branched, alkylene group having from 1 to 6,preferably 1 to 3, especially 3 carbon atoms.

Y represents a hydrogen atom or an alkyl group having up to 6 carbonatoms, and

Z represents a hydrogen atom or one or more alkyl, alkoxy ormercaptoalkyl groups, the alkyl group having from 1 to 6 carbon atoms,or one or more trifluoromethyl groups or halogen atoms.

The new compounds of the invention are generally, with a few exceptions,crystalline solids, having a medium to high melting point. The free baseis usually insoluble or difficultly soluble in water; it is usuallysoluble in chlorinated hydrocarbon solvents, such as chloroform orether. The new aryl substituted piperazinyl alkyl-amino uracils aredepressants of the nervous system of animals such as vertebrates andmammals and lower the blood pressure of such animals. Their mode ofaction is different from that of conventional hypertonics.

The new uracil compounds and their pharmaceutically acceptable salts arealso useful for administration to animals for studying the behaviour ofthe animals and for studying drug effects on the central nervous systemthereof.

In the attached drawing, Diagrams 1 and 2 demonstrate the lowering ofthe systolic and diastolic blood pressure in humans by the applicationof various doses of a typical compound of the invention.

The most preferred aryl-substituted piperazinylalkylamino-uracils,-uracil ethers and -uracil thioethers of the invention are those whichcorrespond to the general Formula I including also the salts of thesecompounds with pharmaceutically acceptable inorganic and organic acids.##SPC2##

In Formula I R¹ and R² each represents a hydrogen atom, a linear, alkylgroup having 1 to 4 carbon atoms or a cycloalkyl, like cyclopentyl orcyclohexyl, or a phenyl group, the methyl group being most preferred.The cycloalkyl group or phenyl groups can be substituted with loweralkyl like methyl;

R³ represents a hydrogen atom, a linear alkyl group having up to 4carbon atoms, a halogen atom, preferably chlorine or bromine, a nitrogroup, a nitroso group, an amino group, an alkylamino group, wherein thealkyl contains 1 to 3 carbon atoms, a dialkylamino group, wherein eachof the alkyl groups contains 1 to 3 carbon atoms, an acylamino groupcontaining from 1 to 4 carbon atoms, a formyl group, anethoxycarbonylamino group or a thiocyanato group, wherein thosecompounds, wherein R³ is hydrogen, a linear alkyl group of 1 to 4 carbonatoms, bromine, an amino group or a diethylamino group are mostpreferred;

X represents an --NH-- group, an --N(C₂ H₅)-- group, an oxygen atom or asulfur atom;

A represents a --CH₂ --CH₂ --CH₂ -- group, a --CH(CH₃)--CH₂ -- group ora --CH₂ --CH(CH₃)-- group, X being in all these cases linked to the leftside of the represented group, i.e. A being linked to X and the nitrogenin the ring;

Z represents a hydrogen atom, a methyl group, one or two methoxy groups,one ethoxy group or a chlorine atom, wherein those compounds, wherein Zstands for one methoxy group, preferably in the o-position are notpreferred.

The present invention provides furthermore a new method for thepreparation of the compounds of the general Formula I above and of thesalts of these compounds with pharmacologically acceptable inorganic ororganic acids.

The method of the invention comprises several embodiments.

In one embodiment a) of the new method a compound of the general FormulaII ##SPC3##

wherein R¹, R², R³, X and A have the meaning set out hereinbefore inconnection with Formula I, and Hal represents a halogen atom, preferablya chlorine or bromine atom is reacted with a phenylpiperazine of thegeneral Formula III or with a salt thereof ##SPC4##

wherein Y and Z have the meaning set out hereinbefore in connection withgeneral Formula I.

In another embodiment b) of the new method a compound of the generalFormula IV ##SPC5##

wherein R¹, R², R³, and Hal have the meaning set out hereinbefore inconnection with embodiment a) of the method is reacted with a compoundof the general Formula V ##SPC6##

wherein A, X, Y and Z have the meaning set out hereinbefore inconnection with Formula I.

Compounds having the general Formula VI ##SPC7##

wherein R¹, R², A, X, Y and Z have the meaning set out hereinbefore inconnection with general Formula I and wherein R⁶ is a halogen atom ornitroso, amino, alkylamino, dialkylamino, acylamino, acyl, formyl,ethoxycarbonylamino, thiocyanato, or the --CONHR⁴ group, wherein R⁴ isdefined above, can advantageously be prepared by an embodiment c) of themethod of the invention, in which the substituent R⁶ is introduced by asuitable substitution reaction into the 5-position of a compound of thegeneral Formula VII ##SPC8##

wherein R¹, R², A, X, Y and Z are defined above in connection withFormula I, to obtain the compounds of Formula I or VI, which can beconverted to their salts, if desired.

In a most preferred embodiment of the new method of the invention forthe production of the new aryl-substitutedpiperazinyl-alkylamino-uracils, -uracil ethers and -uracil thioethers bythe embodiments a) and b) of the method described above, the reaction iseffected at a raised temperature, most advantageously between 50° and150°C. The reaction is preferably carried out in the presence of aninert solution, such as chloroform, benzene, toluene or xylene.Beneficially, an equivalent amount of an auxiliary base, such astriethylamine is added, or, if desired, an excess of the basic startingmaterial of the general Formula III or V, respectively, is used. If thereaction is carried out in the absence of an inert solvent, it isgenerally advantageous, to work in the presence of an excess of saidauxiliary base. In some instances, it is possible to use water as thesolvent in the reaction.

In the embodiment c) of the method of the invention, the varioussubstituents R⁶ are preferably introduced in the following manner:

1. The halogen atom is introduced by halogenation of the compounds ofthe general Formula VII, preferably by treatment of the compound withelemental halogen, such as chlorine or bromine, under halogenationconditions.

2. The alkylamino group is introduced by reaction of the halogensubstituted product, obtained by the foregoing embodiment 1 of themethod, with the desired alkyl-amine.

3. The dialkylamino group is introduced by reaction of the halogensubstituted product, obtained by the foregoing embodiment 1 of themethod, with the desired dialkylamine.

4. The acyl group is introduced by reaction of the compounds of thegeneral Formula VII with an acylation agent containing the desired acylgroup, such as the corresponding aliphatic or aromatic carboxylic acidanhydride or the corresponding carboxylic acid halide.

5. The --CONHR⁴ group is introduced by the reaction of the compounds ofthe general Formula VII with the corresponding isocyanate.

6. The nitroso group is introduced by treatment of the compounds of thegeneral Formula VII with a compound, which yields under reactionconditions the nitroso group, such as i-amylnitrite.

7. The amino group is introduced by reduction of the nitroso group inthe nitroso compounds, produced by the foregoing embodiment 6 of themethod, e.g. by the reaction with dithionite.

8. The acylamino group may be introduced by acylation of the amino groupin the amino substituted compounds, obtained by the foregoing embodiment7 of the method, by treatment with the desired acylation agent, forinstance, with the corresponding aliphatic or aromatic carboxylic acidanhydride or carboxylic acid halide containing the respective acylradical.

9. The ethoxycarbonylamino group is introduced by reacting the acylaminosubstituted compounds obtained by the foregoing embodiment 8 of themethod, with a chloroformic acid ester.

10. The formyl group is introduced by reacting the compounds of thegeneral Formula VII with acetic acid - formic acid anhydride.

11. The thiocyanato group is introduced by treatment of the compounds ofthe general Formula VII with a compound yielding under reactionconditions a thiocyanato group, such as ammonium thiocyanate in thepresence of bromine.

The most preferred method of the invention for the production of thecompounds of the general Formula I above and of their salts withpharmacologically acceptable inorganic or organic acids comprises:

a. Reacting a compound of the general Formula II ##SPC9##

wherein R¹, R², R³, A and X have the significance set out hereinbeforein connection with the general Formula I of the most preferred compoundsand wherein Hal is a chlorine or bromine atom with a phenylpiperazine ofthe general Formula III or with a salt thereof ##SPC10##

wherein Z has the significance set out hereinbefore in connection withthe general Formula I, of the most preferred compounds or

b. Reacting a compound of the general Formula IV ##SPC11##

wherein R¹, R², R³ and Hal have the signficance set out hereinbefore, inconnection with general Formula II, with a compound of the generalFormula V ##SPC12##

wherein A, X and Z have the significance set out hereinbefore inconnection with general preferred Formula I.

Compounds having the general Formula VI ##SPC13##

wherein R¹, R², A, X and Z have the meaning set out hereinbefore inconnection with the preferred general Formula I and wherein R⁶ is ahalogen atom, a nitroso group, an amino group, an alkylamino grouphaving up to 3 carbon atoms, a dialkylamino group having up to 6 carbonatoms, an acylamino group having up to 4 carbon atoms, a formyl group,an ethoxy carbonylamino group or a thiocyanato group, those compoundsbeing most preferred wherein R⁶, is a bromine atom, an amino group or adiethylamino group, are most advantageously prepared by embodiment c) ofthe new method of the invention in which the substituent R⁶ isintroduced by a suitable substitution reaction into the 5-position of acompound corresponding to the general Formula VII ##SPC14##

wherein R¹, R², A, X and Z have the significance set out hereinbefore inconnection with the preferred general Formula I, to obtain the compoundsof Formula I or VI, which can be converted to their respective walls, ifdesired.

The new compounds of the invention, and especially as prepared byembodiments a, b, c, a, b, c of the new method, are, if desired,converted into their pharmacologically acceptable salts by contactingand reacting the free base with the corresponding, desiredpharmacologically acceptable inorganic acid or organic acid.

The production of the pharmacologically acceptable salts of thecompounds of the general Formula I may be effected by dissolving thefree base in a suitable solvent and reacting the dissolved base by theaddition of the required amount, usually the equivalent amount of thedesired acid and recovering the salt of the compound. For the productionof the difficulty soluble salts of the base, it is possible to use forthe reaction with the acid, instead of the free base, a soluble saltthereof. In the case of difficulty soluble acids, it is often beneficialto use a soluble salt of the acid for the reaction.

Suitable organic and inorganic acids comprise for instance, acetic acid,oxalic acid, maleic acid, fumaric acid, tartaric acid, benzoic acid,pamoic acid, salicylic acid, polygalacturonic acids, polyvinylcarboxylicacids, hydrochloric acid, sulfuric acid, phosphoric acid, amido sulfonicacid, methane sulfonic acid. Hydrochloric acid and sulfuric acid aregenerally the most preferred acids for the formation of thepharmacologically acceptable salts.

In similar manner, the free base of the uracil compounds of theinvention may be produced from the corresponding salt of the compound byhydrolysis, e.g. by adding at least a molar equivalent of sodiumhydroxide or other suitable strong base in aqueous solution, followed byextraction or separation of the free base in usual manner.

As disclosed above, the invention comprises salts of the new uracilcompounds, which are readily soluble in water and salts which aredifficultly soluble in water, whereby the salts of lesser solubility inwater are especially useful for the retard forms of the compounds of theinvention.

Typical compounds of the invention include those described belowincluding those in Table I which shows melting points and yields of thecompounds illustrated in the examples.

In the reaction of the invention in embodiment a), it is desirable forbest yields to use the reactants of formula II and III in a mole ratioof 1 to 2.2 to about 2.5, respectively and in embodiment b) thereactants of formula IV and V in a mole ratio of 1 to 2.2 to 2.5,respectively. In embodiment c) the reactants are desirably used in a 1to 1 mole ratio, with the base in a 10 to 20 time excess.

                                      Table I                                     __________________________________________________________________________    Compounds of Examples 1 to 43                                                 Compound of                                        Melting                                                                              Yield               Example No.                                                                           R.sup.1                                                                            R.sup.2                                                                           R.sup.3                                                                              X     A          Y Z       ° C                                                                           %)                  __________________________________________________________________________    1       CH.sub.3                                                                           CH.sub.3                                                                          H      NH    --CH.sub.2 --CH.sub.2 --CH.sub.2 --                                                      H p-CH.sub.3                                                                            175    74                  2       CH.sub.3                                                                           CH.sub.3                                                                          H      NH    --CH.sub.2 CH.sub.2 --CH.sub.2 --                                                        H o-Cl    150    45                  3       CH.sub.3                                                                           CH.sub.3                                                                          H      NH    --CH.sub.2 --CH.sub.2 --CH.sub.2 --                                                      H 2,5-di-OCH.sub.3                                                                      195    52                  4       CH.sub.3                                                                           CH.sub.3                                                                          H      NH    --CH.sub.2 --CH.sub.2 --CH.sub.2 --                                                      H o-OCH.sub.3                                                                           156    77                  5       CH.sub.3                                                                           CH.sub.3                                                                          H      NH    --CH.sub.2 --CH.sub.2 --CH.sub.2 --                                                      H o-OC.sub.2 H.sub.5                                                                    174    65                  6       CH.sub.3                                                                           CH.sub.3                                                                          H      NH    -- CH.sub.2 --CH.sub.2 --CH.sub.2 --                                                     H 2,4-di-OCH.sub.3                                                                      121    72                  7       CH.sub.3                                                                           CH.sub.3                                                                          H      NH    --CH.sub.2 --CH.sub.2 --CH.sub.2 --                                                      H m-OCH.sub.3                                                                           148    70                  8       CH.sub.3                                                                           CH.sub.3                                                                          H      NH    --CH.sub.2 --CH.sub.2 --CH.sub.2 --                                                      H p-OCH.sub.3                                                                           155    60                  9       CH.sub.3                                                                           CH.sub.3                                                                          H      O     --CH.sub.2 --CH.sub.2 --CH.sub.2 --                                                      H o-OCH.sub.3                                                                           146    58/88               10      CH.sub.3                                                                           CH.sub.3                                                                          H      NH    --CH.sub.2 --CH.sub.2 --                                                                 H o-OC.sub.3                                                                            169    80                  11      CH.sub.3                                                                           CH.sub.3                                                                          H      NH    --CH.sub.2 --CH.sub.2 --CH.sub.2 --                                                      H H       114    63                  12      CH.sub.3                                                                           CH.sub.3                                                                          H      NH    --CH.sub.2 --CH.sub.2 --CH.sub.2 --                                                      H o-CH.sub.3                                                                            162    72                  13      CH.sub.3                                                                           CH.sub.3                                                                          H      NH    --CH.sub.2 --CH.sub.2 --CH.sub.2 --                                                      H p-Cl    178    46                  14      CH.sub.3                                                                           CH.sub.3                                                                          CH.sub.3                                                                             NH    --CH.sub.2 --CH.sub.2 --CH.sub.2 --                                                      H o-OCH.sub.3                                                                           120    66                  15      CH.sub.3                                                                           CH.sub.3                                                                          n-C.sub. 4 H.sub.9                                                                   NH    --CH.sub.2 --CH.sub.2 --CH.sub.2 --                                                      H o-OCH.sub.3                                                                           Base   54 2)                                                                  oil 2)3)                   16      CH.sub.3                                                                           CH.sub.3                                                                          NO.sub.2                                                                             NH    --CH.sub.2 --CH.sub.2 --CH.sub.2 --                                                      H o-OCH.sub.3                                                                           162    82                  17      CH.sub.3                                                                           CH.sub.3                                                                          H      NH    --CH--CH-- H o-OCH.sub.3                                                                           166    51                                                |                                                                    CH.sub.3                                        18      CH.sub.3                                                                           CH.sub.3                                                                          Br     NH    --CH.sub.2 --CH.sub.2 --CH.sub.2 --                                                      H o-OCH.sub.3                                                                           197 10)                                                                              56                  19      CH.sub.3                                                                           CH.sub.3                                                                          NO     NH    --CH.sub.2 --CH.sub.2 --CH.sub.2 --                                                      H o-OCH.sub.3                                                                           ca.125 77                  20      CH.sub.3                                                                           CH.sub.3                                                                          NH.sub.2                                                                             NH    --CH.sub.2 --CH.sub.2 --CH.sub.2 --                                                      H o-OCH.sub.3                                                                           123    79                  21      CH.sub.3                                                                           CH.sub.3                                                                          NHCOC.sub.2 H.sub.5                                                                  NH    --CH.sub.2 --CH.sub.2 --CH.sub.2 --                                                      H o-OCH.sub.3                                                                           132    84                  22      CH.sub.3                                                                           H   H      NH    --CH.sub.2 --CH.sub.2 --CH.sub.2 --                                                      H o-OCH.sub.3                                                                           232    41                                                CH.sub.3                                                                      |                                      23      CH.sub.3                                                                           CH.sub.3                                                                          H      NH    --CH--CH.sub.2 --                                                                        H o-OCH.sub.3                                                                           238 9)                     24      C.sub.6 H.sub.11                                                                   H   H      NH    --CH.sub.2 --CH.sub.2 --CH.sub.2 --                                                      H o-OCH.sub.3                                                                           218    38                  25      C.sub.6 H.sub.11                                                                   H   C.sub.4 H.sub.9                                                                      NH    --CH.sub.2 --CH.sub.2 --CH.sub.2 --                                                      H o-OCH.sub.3                                                                           155    66                  25      C.sub.4 H.sub.9                                                                    H   H      NH    --CH.sub.2 --CH.sub.2 --CH.sub.2 --                                                      H o-OCH.sub.3                                                                           204    50                  25      H    H   H      NH    --CH.sub.2 --CH.sub.2 --CH.sub.2 --                                                      H o-OCH.sub.3                                                                           270    30                  26      CH.sub.3                                                                           CH.sub.3                                                                          CH=O   NH    --CH.sub.2 --CH.sub.2 --CH.sub.2 --                                                      H o-OC.sub.3                                                                            122    40                  27      CH.sub.3                                                                           CH.sub.3                                                                          NHCOOC.sub.2 H.sub.5                                                                 NH    --CH.sub.2 --CH.sub.2 --CH.sub.2 --                                                      H o-OCH.sub.3                                                                           125    60                  28      CH.sub.3                                                                           CH.sub.3                                                                          SCN    NH    --CH.sub.2 --CH.sub.2 -- CH.sub.2 --                                                     H o-OCH.sub.3                                                                           188    80                  29      C.sub.6 H.sub.5                                                                    H   H      NH    --CH.sub.2 --CH.sub.2 --CH.sub.2 --                                                      H o-OCH.sub.3                                                                           186    80                  30      H    C.sub.6 H.sub.5                                                                   H      NH    --CH.sub.2 --CH.sub.2 --CH.sub.2 --                                                      H o-OCH.sub.3                                                                           218    18                  31      CH.sub.3                                                                           CH.sub.3                                                                          N(C.sub.2 H.sub.5).sub.2                                                             NH    --CH.sub.2 --CH.sub.2 --CH.sub.2 --                                                      H o-OCH.sub.3                                                                           oil 4) 46                  32      CH.sub.3                                                                           CH.sub.3                                                                          CONHC.sub.6 H.sub.5                                                                  NH    --CH.sub.2 --CH.sub.2 --CH.sub.2 --                                                      H o-OCH.sub.3                                                                           165 5) 81                  33      CH.sub.3                                                                           CH.sub.3                                                                          COCH.sub.3                                                                           NH    --CH.sub.2 --CH.sub.2 --CH.sub.2 --                                                      H o-OCH.sub.3                                                                            98    40                  34      CH.sub.3                                                                           CH.sub.3                                                                          H      N(C.sub.2 H.sub.5)                                                                  --CH.sub.2 --CH.sub.2 --CH.sub.2 --                                                      H o-OCH.sub.3                                                                           162 6) 75                  35      CH.sub.3                                                                           CH.sub.3                                                                          H      O     --CH.sub.2 --CH.sub.2 --CH.sub.2 --                                                      H o-OCH.sub.3                                                                           oil 7) 78                  36      CH.sub.3                                                                           CH.sub.3                                                                          H      O     --CHCH.sub.2 --                                                                          H H       oil 8) 49                                                |                                                                    CH.sub.3                                        37      CH.sub.3                                                                           CH.sub.3                                                                          H      O     --CHCH.sub.2 --                                                                          H p-CH.sub.3                                                                            120    70                                                |                                                                    CH.sub.3                                        38      CH.sub.3                                                                           CH.sub.3                                                                          H      O     --CHCH.sub.2 --                                                                          H p-Cl    163    80                                                |                                                                    CH.sub.3                                        39      CH.sub.3                                                                           CH.sub.3                                                                          H      S     --CH--CH.sub.2 --                                                                        H o-OCH.sub.3                                                                           148    78                                                |                                                                    CH.sub.3                                        40      CH.sub.3                                                                           CH.sub.3                                                                          H      S     --CH--CH.sub.2 --                                                                        H H       230 9) 59                                                |                                                                    CH.sub.3                                        41      CH.sub.3                                                                           CH.sub.3                                                                          H      S     --CH--CH.sub.2 --                                                                        H m-CH.sub.3                                                                            217 9) 48                                                |                                                                    CH.sub.3                                        42      CH.sub.3                                                                           CH.sub.3                                                                          H      S     --CH-- CH.sub.2 --                                                                       H p-CH.sub.3                                                                            152    45                                                |                                                                    CH.sub.3                                        43      CH.sub.3                                                                           CH.sub.3                                                                          H      S     --CH--CH.sub.2 --                                                                        H p-Cl    152    28                                                |                                                                    CH.sub.3                                        __________________________________________________________________________    Remarks to Table I                                                            1) = Melting point of the free base, unless noted otherwise                   2) = Picrate has melting point of 173 - 175° C                         3) = Oxalate has melting point of 155° C                                    Dioxalate has melting point of 173° C                                  Trihydrochloride has melting point of 192° C                      4) = Trihydrochloride × 1 H.sub.2 O has melting point of                     231° C                                                            5) = Hydrochloride has melting point of 225° C                         6) = Dihydrochloride sinters at 162° C and above                       7) = Dihydrochloride has melting point of 220° C                       8) = Dihydrochloride sinters at 170° C and above                       9) = Dihydrochloride                                                          10) =                                                                              Dihydrobromide                                                       

Further illustrative compounds of the invention include the following.

    Example                                                                            R.sup.1                                                                             R.sup.2                                                                             R.sup.3                                                                              X    A       Y        Z                               __________________________________________________________________________    44   butyl methyl                                                                              H      NH   --(CH.sub.2).sub.3 --                                                                 H        p-CH.sub.3                      45   methyl                                                                              hexyl H      NH   --(CH.sub.2).sub.2 --                                                                 H        o-Cl                            46   ethyl methyl                                                                              H      NH   --(CH.sub.2).sub.2 --H                                                                o-OCH.sub.2 CH.sub.3                     47   methyl                                                                              isopropyl                                                                           H      NH   --(CH.sub.2).sub.2 --H                                                                o-CH.sub.2 CH.sub.3                      48   methyl                                                                              pentyl                                                                              H      NH   --(CH.sub.2).sub.2 --                                                                 H        o-CF.sub.3                      49   methyl                                                                              methyl                                                                              benzyl NH   --(CH.sub.2).sub.2 --                                                                 H        o-Br                            50   methyl                                                                              methyl                                                                              phenyl NH   --(CH.sub.2).sub.2 --                                                                 2-CH.sub.3                                                                             p-CH.sub.3                      51   methyl                                                                              methyl                                                                              OCH--  NH   --(CH.sub.2).sub.2 --                                                                 H        p-CH.sub.3                      52   methyl                                                                              methyl                                                                              NHCOOC.sub.3 H.sub.7                                                                 NH   --(CH.sub.2).sub.2 --                                                                 H        p-CH.sub.3                      53   methyl                                                                              methyl                                                                              N(C.sub.3 H.sub.7).sub.2                                                             NH   --(CH.sub.2).sub.2 --                                                                 H        p-CH.sub.3                      54   isopropyl                                                                           H     H      NH   --(CH.sub.2).sub.4 --                                                                 3-CH.sub.2 --CH.sub.3                                                                  p-CH.sub.3                      55   allyl methyl                                                                              H      NH   --(CH.sub.2).sub.3 --                                                                 2-(CH.sub.3 ).sub.2 --CH.sub.2                                                         p-CH.sub.3                      56   propenyl                                                                            methyl                                                                              H      NH   --(CH.sub.2).sub.3 --                                                                 3-(CH.sub.3).sub.2 --CH.sub.2                                                          p-CH.sub.3                      57   methyl                                                                              isobutyl                                                                            H      O    --(CH.sub.2).sub.3 --                                                                 2-CH.sub.3                                                                             p-CH.sub.3                      58   ethyl H     H      NH   --CH.sub.2 CH:CH--                                                                    H        H                               59   methyl                                                                              methyl                                                                              H      N(CH.sub.3)                                                                        --(CH.sub.2).sub.3 --                                                                 H        H                               60   methyl                                                                              H     allyl  NH   --(CH.sub.2).sub.3 --                                                                 H        p-Cl                            61   methyl                                                                              methyl                                                                              NO     NH   --(CH.sub.2).sub.3 --                                                                 H        o-CH.sub.3                      __________________________________________________________________________

The following examples illustrate the invention, but are not to beconstrued as limiting the same.

EXAMPLE 11,3-Dimethyl-4-(γ-[4-(p-tolyl)-piperazinyl-(1)]-propylamino)-uracil

26 g (0.11 mole) of p-tolylpiperazinecarbonate and 12 g (0.05 mole) of1,3-dimethyl-4-(γ-chloropropylamino)uracil were dissolved in 150 mlethanol. After the addition of 200 ml toluene, the ethanol was distilledoff, and the mixture was boiled under reflux for 2 hours and filteredwhile still hot. The solvent was removed from the filtrate in vacuo andthe residue boiled with ether and filtered. The residue thus obtainedwas thereafter further purified by recrystallization from an acetonesolution in a Thielepape device. The recrystallization may also beeffected from a methanol solution.

11 g of1,3-dimethyl-4-(γ-[4-(p-tolyl)-piperazinyl(1)]-propylamino)-uracil,having a melting point of 174°-175°C, were obtained, corresponding to ayield of 74%.

EXAMPLE 21,3-Dimethyl-4-(γ-[4-(o-chlorophenyl)-piperazinyl(1)]-propylamino)-uracil

11.6 g (0.05 mole) of 1,3-dimethyl-4-(γ-chloropropylamino)-uracil and 34g (0.15 mole) of o-chlorophenylpiperazine-carbonate were boiled for 3hours in 350 ml xylene under reflux. After cooling the mixture, 200 ml6n sodium hydroxide solution were added and the separated aqueous phaseextracted with chloroform. The chloroform extract and the xylene phasewere thereafter combined, dried over magnesium sulfate, filtered and thesolvents evaporated. The brown residue was then purifiedchromatographically in a column of silica gel "neutral", (Merck A.G.)having a particle size of 0.05-0.2 mm. The flow agent was a mixture ofethyl acetate, methanol and concentrated aqueous ammonia in a ratio of20:4:1. The light brown material thus obtained was recrystallized frommethanol with the addition of activated carbon. 8.5 g of1,3-dimethyl-4-(γ-[4-(o-chlorophenyl)-piperazinyl(1)]-propylamino)-uracil,having a melting point of 150°-151°C, were thus obtained, representing ayield of 45%.

EXAMPLE 31,3-Dimethyl-4-(γ-[4-(2,5-dimethoxyphenyl)piperazinyl-(1)]-propylamino)-uracil

29.5 g (0.1 mole) of the dihydrochloride of2,5-dimethoxyphenyl-piperazine were dissolved in water, and the solutionwas made alkaline by the addition of sufficient 6 n aqueous sodiumhydroxide. The solution was then extracted with chloroform and thechloroform evaporated from the extract. To the free base thus obtainedwere added 11.6 g (0.05 mole) of1,3-dimethyl-4-(-chloropropylamino)-uracil and 500 ml xylene. Themixture was heated for 2 hours under reflux and the xylene distilled offin vacuo. The residue was purified chromatographically in a column ofsilica gel "neutral" (Merck A.G.) with the use of a mixture of ethylacetate, methanol and concentrated aqueous ammonia in a ratio of 20:4:1as the flow agent. The purification may also be effected byrecrystallization from methanol, preferable with the use of theThielepape device.

11 g of1,3-dimethyl-4-(γ-[4-(2,5-dimethoxyphenyl)-piperazinyl-(1)]-propylamino)-uracilhaving a melting point of 194°-195°C were obtained, representing a yieldof 52%.

EXAMPLE 41,3-Dimethyl-4-(γ-[4-(o-methoxyphenyl)piperazinyl)-(1)]-propylamino)-uracil

a. 28.2 g (0.11 mole of o-methoxyphenylpiperazinecarbonate and 11.6 g(0.05 mole) of 1,3-dimethyl-4-(γ-chloropropylamino)-uracil were boiledunder reflux for 5 hours in 150 ml water. The cooled aqueous solutionwas made alkaline by the addition of sufficient 6 n aqueous sodiumhydroxide and extracted with chloroform. The chloroform extract wasdried and the chloroform evaporated. The residue was crystallized from200 ml ether and the crystalline phase was filtered off by suction. 14.8g1,3-dimethyl-4-(γ-[4-(o-methoxyphenyl)-piperazinyl-(1)]-propylamino)-uracil,having a melting point of 156°C, were obtained, representing a yield of77%.

The product was obtained in similarly good yield by the extraction ofthe aqueous reaction mixture with hot toluene and precipitation of thecompound from the toluene solution by the addition of petroleum ether(boiling in the range from 50°-70°C.).

b) 600 g (2.36 moles) of o-methoxyphenyl-piperazinecarbonate weredissolved with stirring and heating in 3 l xylene, with the evolution ofcarbon dioxide. A solution of 242 g (1.04 mole)1,3-dimethyl-4-(γ-chloropropylamino)-uracil in 1.5 l methanol was thenadded drop by drop, while maintaining the temperature of the xylenesolution at 120°C, whereby the methanol continuously distilled off.After completion of the addition of the methanol solution, the reactionmixture was heated to and stirred at 140°C for one more hour, whereafterthe solution, while still at this temperature, was filtered by suctionto separate the o-methoxyphenyl-piperazine hydrochloride precipitatedduring the reaction. The filter residue was washed with hot xylene.

312 g of a brown reaction product (representing 81% yield) wererecovered by cooling the filtrate, filtering off the precipitate bysuction, concentrating the filtrate thus obtained by partialevaporation, cooling again and filtering by suction the additionalquantities of precipitate.

The raw product was purified by recrystallization from ethanol with theaddition of activated carbon to result in 280 g1,3-dimethyl-4-(γ-[4-(o-methoxyphenyl)-piperazinyl-(1)]-propylamino)-uracilof a melting point of 156°C corresponding to a yield of 70%.

Purification of the raw product by boiling in acetone resulted insimilar yields.

c. 20.6 g (0.083 mole) ofN-(o-methoxyphenyl)-N'-(3-aminopropyl)-piperazine and 15.7 g (0.09 mole)of 1,3-dimethyl-4-chlorouracil were boiled for 15 hours in 100 mltriethylamine. The excess triethylamine was then distilled off in vacuoand the residue was dissolved in 300 ml 1n hydrochloric acid withsubsequent filtration. The filtrate thus obtained was cooled with iceand 2 n aqueous ammonic solution was slowly added with stirring. As soonas the first precipitation appeared, a few crystals of the desiredproduct were added to the solution. The ammoniacal suspension wasstirred for one more hour, the precipitate filtered off by suction andwashed with 200 ml water. The material was purified by recrystallizationfrom ethanol with the addition of activated carbon. In this manner 24.2g1,3-dimethyl-4-(γ-[4-(o-methoxyphenyl)-piperazinyl-(1)]-propylamino)-uracilhaving a melting point of 156°C were obtained corresponding to a yieldof 75%. The purification may also be effected by boiling the material inacetone to result in similar yields.

The new compounds described in the following Examples 5 to 8 wereproduced by the methods described in the preceding examples 3 and 4bwith the substitution of the correspondingly substituted startingmaterials.

EXAMPLE 51,3-Dimethyl-4-(γ-[4-(o-ethoxyphenyl)-piperazinyl-(1)]-propylamino)-uracil

was prepared in a yield of 65% and the compound had a melting point of173°-174°C.

EXAMPLE 61,3-Dimethyl-4-(γ-[4-(2,4-dimethoxyphenyl)-piperazinyl-(1)]-propylamino)-uracil

was prepared in a yield of 72% and had a melting point of 120°-122°C.

EXAMPLE 71,3-Dimethyl-4-(γ-[4-(m-methoxyphenyl)-piperazinyl-(1)]-propylamino)-uracil

was prepared in a yield of 70% and had a melting point of 147°-148°C.

EXAMPLE 81,3-Dimethyl-4-(γ-[4-(p-methoxyphenyl)-piperazinyl-(1)]-propylamino)-uracil

was prepared in a yield of 60% and had a melting point of 155°-156°C.

EXAMPLE 91,3-Dimethyl-4-(γ-[4-(o-methoxyphenyl)-piperazinyl-(1)]-propyloxy)-uracil

a. 3.1 g (0.011 mole) of 1,3-dimethyl-4-(γ-bromopropyloxy)-uracil and6.7 g (0.03 mole) of o-methoxyphenylpiperazinecarbonate were heated for3 hours in 100 ml xylene under reflux. The solution was then cooled andthe precipitated hydrobromide of the o-methoxyphenylpiperazine wasfiltered off and washed with benzene. The solvent was distilled off invacuo from the filtrate and the residue was taken up for the subsequentchromatography in a small quantity of a flow agent consisting of amixture of ethyl acetate, methanol and concentrated aqueous ammonia in aratio of 20:4:1. The chromatography was effected in 280 g silica gel"neutral" (Merck A.G.), having a particle size of 0.05 to 0.2 mm. Inthis manner, 3.8 g1,3-dimethyl-4-(γ-[4-(o-methoxyphenyl)-piperazinyl-(1)]-propyloxy)-uracilwere obtained, representing a yield of 88%. Recrystallized from ethylacetate, the compound had a melting point of 146°-148°C.

b. 3.5 g of a 33% dispersion of sodium metal in toluene (containingabout 0.05 mole sodium) were diluted with 35 ml of absolutely drytoluene and 9.5 g (0.035 mole) ofN-(o-methoxyphenyl)-N'-(γ-hydroxypropyl)-piperazine were added theretowith stirring. When the violent exothermic reaction had subsided, 8.8 g(0.05 mole) of 1,3-dimethyl-4-chloro-uracil were added in small portionsto the reaction mixture at room temperature. Thereby a thick suspensionwas formed, which was heated with reflux for 1.5 hours. After cooling,80 ml 2 n hydrochloric acid were added, and the mixture was extractedthree times with 25 ml benzene each time for the removal of unreactedchlorouracil. Thereafter, the p_(H) was adjusted to 8 by the addition of1 n aqueous sodium hydroxide and the mixture extracted three times with100 ml chloroform each. The chloroform extracts were combined and driedand the chloroform evaporated. The residue was recrystallized fromethanol to result in 8.3 g of 1,3-dimethyl-4-(γ-[4-(o-methoxyphenyl)-piperazinyl-(1)]-propyloxy)-uracil having amelting point of 145°-148°C and representing a yield of 58%.

EXAMPLE 101,3-Dimethyl-4-(β-[4-(o-methoxyphenyl)-piperazinyl-(1)]-ethylamino)-uracil

6.6 g (0.03 mole) of 1,3-dimethyl-4-(β-chloroethylamino)-uracil and 15.6g (0.07 mole) of o-methoxyphenyl-piperazine carbonate were heated for 2hours in 200 ml xylene with reflux. To the cooled reaction mixture wereadded 150 ml 6 n aqueous sodium hydroxide, and the organic phase wasseparated. The aqueous alkaline phase was extracted with chloroform. Theorganic phases were combined, dried over magnesium sulfate and theorganic solvent evaporated in vacuo. The residue was briefly boiled withether, and the crystals thus formed were filtered off and recrystallizedfrom acetone.

9 g1,3-dimethyl-4-(β-[4-(o-methoxyphenyl)-piperazinyl-(1)]-ethylamino)-uracilare obtained, having a melting point of 169°C and representing a yieldof 80%.

EXAMPLE 111,3-Dimethyl-4-(γ-[4-phenyl-piperazinyl-(1)]-propylamino)-uracil

25 g (0.14 mole) of 1,3-dimethyl-4-chlorouracil, 31.4 g (0.14 mole) ofN'-phenyl-N-(3-aminopropyl)-piperazine and 50 ml of triethylamine wereboiled with reflux for 16 hours in 150 ml chloroform. For the removal ofunreacted chloro-uracil, the chloroform and triethylamine wereevaporated in vacuo, the residue dissolved in 200 ml chloroform and thesolution thus obtained was extracted twice with 10 ml each of 2 nhydrochloric acid. To the combined aqueous extracts were added 100 ml of6 n aqueous sodium hydroxide and the solution extracted twice withchloroform. The combined chloroform extracts were freed from chloroformand the residue was crystallized by rubbing in the presence of ether.The crystals were recrystallized from 150 ml ethyl acetate to result in32 g of1,3-dimethyl-4-(γ-[4-phenyl-piperazinyl-(1)]-propylamino)-uracil, havinga melting point of 114°C and representing a yield of 63%.

EXAMPLE 121,3-Dimethyl-4-(γ-[4-(o-tolyl)-piperazinyl-(1)]-propylamino)-uracil

A mixture of 5.3 g (0.03 mole) of 1,3-dimethyl-4-chlorouracil and 7.0 g(0.03 mole) of N-(o-tolyl)-N'-(3-aminopropyl)-piperazine in 10 mltriethylamine were boiled for 10 minutes with reflux. The excesstriethylamine was then removed in vacuo and the residue dissolved in 70ml chloroform. The solution was then extracted three times with 40 mleach of 2 n hydrochloric acid. The combined aqueous-acid phases werethen made alkaline by the addition of 40 ml 6 n aqueous sodium hydroxideand extracted with chloroform. The chloroform extract was dried and thechloroform evaporated, leaving 11 g of an oil, which soon thereaftercrystallized. After recrystallization from benzene, 8.1 g of1,3-dimethyl-4-(γ-[4-(o-tolyl)-piperazinyl-(1)]-propylamino)-uracil wereobtained, having a melting point of 162°C and representing a yield of72%.

EXAMPLE 131,3-Dimethyl-4-(γ-[4-(p-chlorophenyl)-piperazinyl-(1)]-propylamino)-uracil

3.1 g (0.017 mole) of 1,3-dimethyl-4-chlorouracil, 4.3 g (0.017 mole) ofN-(p-chlorophenyl)-N'-(γ-aminopropyl)-piperazine and 10 ml triethylaminewere heated for 1.5 hours with reflux. The excess triethylamine was thenremoved in vacuo and the residue was dissolved in 50 ml chloroform. Thechloroform solution was extracted three times with 50 ml each of 2 nhydrochloric acid. The combined acid phases were washed with chloroform,made alkaline with 6 n aqueous sodium hydroxide and extracted threetimes with 50 ml each of chloroform. The chloroform extracts werecombined, dried and the chloroform evaporated. The residue thus obtainedamounted to 5.9 g. After recrystallization from ethanol, 3.3 g of1,3-dimethyl-4-(γ-[4-(p-chlorophenyl)-piperazinyl-(1)]-propyl-amino)-uracil,having a melting point of 178°-179°C were obtained, representing a yieldof 46%.

EXAMPLE 141,3,5-Trimethyl-4-(γ-[4-(o-methoxyphenyl)-piperazinyl-(1)]-propylamino)-uracil

5.6 g (0.03 mole) of 1,3,5-trimethyl-4-chlorouracil and 17.5 g (0.07mole) of N-(o-methoxyphenyl)-N'(γ-aminopropyl)-piperazine were boiledfor 30 hours in 70 ml xylene with reflux. TheN-(o-methoxyphenyl)-N'-(γ-aminopropyl)-piperazine hydrochloridecrystallizing upon cooling of the reaction mixture, was filtered off andwashed with hot benzene. The filtrate was freed from the solvent invacuo and the residue chromatographically purified in a stationarycolumn of 350 g silica gel "neutral" (Merck A.G.) of a particle size of0.05 to 0.2 mm with the use of a mixture of 10 parts chloroform and 1part ethanol as the flow agent. 8 g of1,3,5-trimethyl-4-(γ-[4-(o-methoxyphenyl)-piperazinyl-(1)]-propylamino)-uracil,having a melting point of 120°-121°C were obtained, representing a yieldof 66%.

EXAMPLE 151,3-Dimethyl-4-(γ-[4-(o-methoxyphenyl)-piperazinyl-(1)]-propylamino)-5-n-butyl-uracil

7.0 g (0.03 mole) of 1,3-dimethyl-4-chloro-5-n-butyl-uracil and 17.5 g(0.07 mole) of N-(o-methoxyphenyl)-N'(γ-aminopropyl)-piperazine wereboiled in 70 ml xylene for 5 days with reflux. The hydrochloride of theN-(o-methoxyphenyl)-N'-(γ-aminopropyl)-piperazine, crystallizing uponcooling of the reaction mixture, was filtered off by suction and thefiltrate was evaporated. The residue was chromatographically purified ina stationary column of silica gel "neutral" (Merck A.G.) of a particlesize of 0.02 to 0.5 mm, with the use of a mixture of 10 parts chloroformand 1 part ethanol as the flow agent. In this manner, 11.4 g of a brownoil were obtained, which was taken up in 250 ml benzene. After additionof a saturated solution of picric acid in benzene, the precipitateformed thereby was permitted to settle and the benzene was decanted. Thesolid residue was recrystallized from ethanol by help of a Thielepapedevice. In this manner 11 g of the picrate of 1,3-dimethyl-4-(γ-[4-(o-methoxyphenyl)-piperazinyl-(1)]-propylamino)-5-n-butyl-uracil,having a melting point of 173°-175°C were obtained, corresponding to ayield of 54%.

EXAMPLE 161,3-dimethyl-4-(γ-[4-(o-methoxyphenyl)-piperazinyl-(1)]-propylamino)-5-nitro-uracil

To a solution of 11 g (0.05 mole) of1,3-dimethyl-4-chloro-5-nitro-uracil in 150 ml benzene was added drop bydrop at room temperature and with stirring a solution of 32 g (0.1 mole)of N-(o-methoxyphenyl)-N'-(γ-aminopropyl)-piperazine. At first a hard tostir precipitate was formed, which dissolved after completion of theaddition of the second solution. Thereafter, the hydrochloric of thepiperazine compound precipitated in crystalline form. The reactionmixture was then boiled for aabout 15 minutes and filtered aftercooling. The filtrate was evaporated and the residue recrystallized fromalcohol.

17.7 g of1,3-dimethyl-4-(γ-[4-(o-methoxyphenyl)-piperazinyl-(1)]-propylamino-5-nitrouracil,having a melting point of 160°-162°C were obtained, representing a yieldof 82%.

EXAMPLE 171,3-Dimethyl-4-(β-[4-(o-methoxyphenyl)-piperazinyl-(1)]-propylamino)-uracil

A mixture of 4 g (0.023 mole) of 1,3-dimethyl-4-chloro-uracil and 12 g(0.046 mole) of 1-amino-2-[4-(o-methoxyphenyl)-piperazinyl-(1)]-propanewas boiled for 5 hours in 300 ml xylene with reflux. After cooling, theprecipitate was filtered off and washed with hot benzene. The combinesfiltrate and washings were evaporated in vacuo and chromatographicallypurified in a column of silica gel "neutral" (Merck A.G.) of a particlesize of 0.05°-0.2° mm. The flow agent was a mixture of ethyl acetate,methanol and concentrated aqueous ammonia in a ratio of 20:4:1. Thebrown product thus obtained (5.5 g) was recrystallized from 70 mlethylacetate in the presence of activated carbon.

4.5 g of1,3-dimethyl-4-(β-[4-(o-methoxyphenyl)-piperazinyl-(1)]-propylamino)-uracil,having a melting point of 165°-166°C were obtained, representing a yieldof 51%.

EXAMPLE 181,3-Dimethyl-4-(γ-[4-(o-methoxyphenyl)-piperazinyl-(1)]-propylamino)-5-bromo-uracil-dihydrobomide

10 g (0.026 mole) of1,3-dimethyl-4-(γ-[4-(o-methoxyphenyl)-piperazinyl-(1)]-propylamino)-uracilwere dissolved in 30 ml glacial acetic acid and a mixture of 4.5 gbromine in 30 ml glacial acetic acid was added drop by drop at 0°C andwith stirring within 30 minutes. After stirring the reaction mixture for30 additional minutes, the crystalline precipitate was filtered off bysuction and washed with a mixture of glacial acetic acid and ether. 9.2g of1,3-dimethyl-4-(γ-[4-(o-methoxyphenyl)-piperazinyl-(1)-]-propylamino)-5-bromo-uracil-dihydrobromidehaving a melting point of 196°-199°C were obtained, representing a yieldof 56%.

EXAMPLE 191,3-Dimethyl-4-(γ-[4-(o-methoxyphenyl)-piperazinyl-(1)]-propylamino)-5-nitroso-uracil

Into the solution of 7.7 g (0.02 mole) of1,3-dimethyl-4-(γ-[4-(o-methoxyphenyl)-piperazinyl-(1)]-propylamino)-uraciland 6 ml i-amylnitrite in 100 ml of a 1:1 mixture of chloroform andacetone were added drop by drop with cooling by ice 20 ml of a saturatedsolution of hydrochloric acid in ethanol. The white precipitate, formedin the red solution, was filtered off by suction and washed withacetone. The solid product thus obtained was hygroscopic andrecrystallized from methanol to result in 9 g of1,3-dimethyl-4-(γ-[4-(o-methoxyphenyl)-piperazinyl-(1)]-propylamino)-5-nitroso-uracilin the form of the trihydrochloride containing 3 moles of crystal water.The product decomposes at 165°C. The yield was 77%.

EXAMPLE 201,3-Dimethyl-4-(γ-[4-(o-methoxyphenyl)-piperazinyl-(1)]-propylamino)-5-amino-uracil

6.1 g (0.012 mole) of1,3-dimethyl-4-(γ-[4-(o-methoxyphenyl)-piperazinyl-(1)]-propylamino)-5-nitroso-uraciltrihydrochloride were dissolved in 30 ml ice water and a solution of 6 gsodiumdithionite in 30 ml ice water was thereto and the mixture stirredat 0°C for 10 minutes. The yellow, clear solution was underlaid with 50ml chloroform and the solution was made alkaline by the addition ofsufficient ice cooled 6 n aqueous sodium hydroxide. Care was takenthereby, that the temperature did not rise above +3°C. The phases wereseparated, the chloroform phase was dried and the chloroform evaporatedat room temperature in a rotary evaporator.

The residue was crystallized by the addition of ether and filtered offby suction. 3.7 g of1,3-dimethyl-4-(γ-[4-(o-methoxyphenyl)-piperazinyl-(1)]-propylamino-5-amino-uracil,having a melting point of 122°-124°C, were obtained, representing ayield of 79%. The solid substance decomposed.

EXAMPLE 211,3-Dimethyl-4-(γ-[4-(o-methoxyphenyl)-piperazinyl-(1)]-propylamino)-5-propionylamino-uracil

To 15 ml propionic acid anhydride were added in small portions at roomtemperature with stirring 5 g (0.0125 mole) of1,3-dimethyl-4-(γ-[4-(o-methoxyphenyl)-piperazinyl-(1)]-propylamino)-5-amino-uracil.After several minutes, crystals formed in the clear solution. Thereaction mixture was then diluted with 150 ml ether and the precipitatewas filtered off by suction. The filter residue was purified in a columnof 300 g silica gel "neutral" (Merck A.G.) with the use of a mixture ofethyl acetate, methanol and concentrated aqueous ammonia in a ratio of20:4:1 by volume. Thereafter, the solvent was completely evaporated fromthe eluted mixture in a rotary evaporator and the residue recrystallizedfrom 25 ml ethyl acetate. 4.8 g of1,3-dimethyl-4-(γ-[4-(o-methoxyphenyl)-piperazinyl-(1)]-propylamino)-5-propionylamino-uracil,having a melting point of 132°-133°C were obtained, representing a yieldof 84%.

EXAMPLE 221-Methyl-4-(γ-[4-(o-methoxyphenyl)-piperazinyl-(1)]-propylamino)-uracil

A mixture of 4.8 g (0.03 mole) of 1-methyl-4-chlorouracil and 15 g (0.06mole) of γ-[4-(o-methoxyphenyl)-piperazinyl-(1)]-propylamine was heatedfor 24 hours at 90°-100°C. The clear solution solidified after coolingto a glass-like mass, which was boiled with the addition of 150 mlethanol to dissolve the solid mass. Thereafter, the crystals formed inthe solution were filtered off by suction, while still hot. The filterresidue was washed with ethanol. 4.6 g1-methyl-4-(γ-[4-(o-methoxyphenyl)-piperazinyl-(1)]-propylamino)-uracil,having a melting point of 230°-233°C, were obtained, representing ayield of 41%.

EXAMPLE 231,3-Dimethyl-4-(β-[4-(o-methoxyphenyl)-piperazinyl-(1)]-α-methylethylamino)-uracil

A mixture of 6 g (0.024 mole) ofN-(o-methoxyphenyl)-N'-(2-aminopropyl)-piperazine, 4.4 g (0.025 mole) of1,3-dimethyl-4-chloro-uracil and 30 ml triethylamine was boiled for 5hours with reflux without regard to undissolved material. Thereafter,the triethylamine was removed in vacuo, and 60 ml 2 n aqueoushydrochloric acid added to the residue, followed by extraction withchloroform. The aqueous acid phase was then made alkaline by theaddition of 2 n aqueous sodium hydroxide, followed by extraction withchloroform. The residue obtained by removal of the chloroform from thechloroform extract, was purified chromatographically in a column ofsilica gel "neutral" with the use of a mixture of 5 parts by volumeethyl acetate and 1 part by volume methanol as the flow agent.

In this manner, 2.6 g of an oil, which solidified to a glass-like mass,were obtained, representing a yield of 34%. The hydrochloride of thecompound, which had the above composition, was recrystallized in asuperheated steam extractor with acetone and found to have a meltingpoint of 238°-240°C.

EXAMPLE 241-Cyclohexyl-4-(γ-[4-(o-methoxyphenyl)-piperazinyl-(1)]-propylamino)-uracil

A mixture of 3.4 g (0.015 mole) of 1-cyclohexyl-4-chloro-uracil and 10 g(0.04 mole) of N-(o-methoxyphenyl)-N'-(γ-aminopropyl)-piperazine washeated for 8 hours to a temperature of about 120°C. The cooled reactionmixture was then shaken with 100 ml 2n aqueous hydrochloric acid and 100ml chloroform; the chloroform phase was discarded. The aqueous, acidsolution was thereafter made alkaline, while cooling with ice, by theaddition of sufficient 2n aqueous sodium hydroxide and extracted withchloroform. The residue obtained, after evaporation of the chloroform,was purified chromatographically in a column of silica gel "neutral",with the use of a mixture of 6 parts by volume chloroform and 1 part byvolume ethanol as the flow agent.

2.5 g1-cyclohexyl-4-(γ-[4-(o-methoxyphenyl)-piperazinyl-(1)]-propylamino)-uracilwere obtained, representing a yield of 38%. The compound wasrecrystallized from a mixture of 30 ml chloroform and 100 ml ethanol andconcentration of the solution by evaporation to 50 ml. The substance hada melting point of 217°-219°C.

EXAMPLE 251-n-Butyl-4-(γ-[4-(o-methoxyphenyl)-piperazinyl-(1)]-propylamino)-uracil

A mixture of 8.2 g (0.04 mole) of 1-butyl-4-chloro-uracil and 20 g (0.08mole) N-(o-methoxyphenyl)-N'-(γ-aminopropyl)-piperazine was heated for 3hours to 140°C. After cooling, the reaction mass was dissolved inchloroform and water. The chloroform phase was separated, evaporated,and the residue recrystallized in a superheated steam extraction frommethanol.

8.3 g1-n-butyl-4-(γ[4-(o-methoxyphenyl)-piperazinyl-(1)]-propylamino)-uracil,having a melting point of 204°C were obtained, representing a yield of50%. The following substances were made by following generally themethod described in the foregoing example 25, but substituting thecorrespondingly substituted starting materials:1-cyclohexyl-4-(γ-[4-(o-methoxyphenyl)-piperazinyl-(1)]-propylamino)-5-n-butyl-uracilwas obtained in a yield of 66% and had a melting point of 155°C.

4-(γ-[4-(o-methoxyphenyl)-piperazinyl-(1)]-propylamino-uracil wasobtained in a yield of 30% and had a decomposition point of about 270°C.

EXAMPLE 261,3-Dimethyl-4-(γ-[4-(o-methoxyphenyl)-piperazinyl-(1)]-propylamino)-5-formyl-uracil

To 50 ml acetic acid anhydride, cooled to 0°C, were added drop by drop25 ml formic acid (98-100%). The mixture was then heated for 15 minutesto 50°C and thereafter quickly cooled to 0°C.

12.5 g (0.032 mole) of1,3-dimethyl-4-γ-[4-(o-methoxyphenyl)-piperazinyl-(1)]-propylamino)-uracilwere then incorporated into the formylation mixture with heating to100°C for 6 hours. The reaction mixture was then cooled and evaporatedat 50°-60°C in vacuo until dry. The residue was then dissolved in water,made alkaline by the addition of 2 n aqueous sodium hydroxide and thesolution extracted with chloroform. The chloroform extract was driedwith sodium sulfate and the solvent removed by evaporation. The residuewas purified chromatographically in a column of silica gel (Merck A.G.)with the use of a mixture of CHCl₃ and C₂ H₅ OH in a ratio of 6:1 byvolume.

In this manner 4.9 g of1,3-dimethyl-4-(γ-[4-(o-methoxyphenyl)-piperazinyl-(1)]-propylamino)-5-formyl-uracil,having a melting point of 122°C were obtained, representing a yield of97%.

EXAMPLE 271,3-Dimethyl-4-(γ[4-(o-methoxyphenyl)-piperazinyl-(1)]-propylamino)-5-carbethoxyamino-uracil

To the solution of 2 g (0.05 mole) of1,3-dimethyl-4-(γ-[4-(o-methoxyphenyl)-piperazinyl-(1)]propylamino)-5-amino-uracilin 10 ml chloroform was added drop by drop, at room temperature, thesolution of 0.5 ml (0.05 mole) chlorocarbonic acid ester in 5 mlchloroform. After 15 minutes, the reaction mixture was washed withsaturated aqueous sodium bicarbonate solution and the organic phase wasseparated, dried and the solvent evaporated. The residue thus obtainedwas crystallized by the addition of acetone and filtered off by suction.In this manner, 1.4 g1,3-dimethyl-4-(γ-[4-(o-methoxyphenyl)-piperazinyl-(1)]-propylamino)-5-carbethoxyamino-uracilwere obtained, representing a yield of 60%. After recrystallization fromacetone, the substance had a melting point of 125°C.

EXAMPLE 281,3-Dimethyl-4-(γ-[4-(o-methoxyphenyl)-piperazinyl-(1)]-propylamino)-5-thiocyanato-uracil

50.5 g (0.14 mole)1,3-dimethyl-4-(γ-[4-(o-methoxyphenyl)-piperazinyl-(1)]-propylamino-uraciland 7.6 g (0.1 mole) ammonium thiocyanate were dissolved in 100 mlglacial acetic acid. The solution was cooled to and held at 10°C, while40 ml 1 n bromine solution in glacial acetic acid were added dropwise.After completion of the bromine addition, the mixture was stirred for 30minutes and the precipitate, formed in the reaction, was filtered off bysuction and washed with glacial acetic acid and ether. The filtrate wasevaporated at 40°C in vacuo until dry and to the residue, thus obtained,was given CHCl₃, H₂ O and concentrated aqueous ammonia. The organicphase was separated and concentrated by evaporation at 40°C in vacuo.After the addition of double the volume of ethanol and renewedevaporation of the solvent, 14.2 g of a precipitate were obtained uponcooling, representing a yield of 80% of1,3-dimethyl-4-(γ-[4-(o-methoxyphenyl)-piperazinyl-(1)]-propylamino)-5-thiocyanato-uracil,which had a melting point of 188°C.

EXAMPLE 291-Phenyl-4-(γ-[4-(o-methoxyphenyl)-piperazinyl-(1)]-propylamino)-uracil

A mixture of 6.7 g (0.03 mole) 1-phenyl-4-chlorouracil and 18 g (0.072mole) N-(o-methoxyphenyl)-N'-(γ-aminopropyl)-piperazine was heated forone half hour at 150°C. The cooled reaction mixture was then stirred for1 hour with 100 ml water and 100 ml chloroform with subsequentseparation of the phases. The chloroform phase was dried and the solventevaporated. The residue thus obtained was purified chromatographicallyin a column of 360 g silica gel "neutral" (Merck A.G.) of a particlesize of 0.05 to 0.2 mm. The flow agent was a mixture of chloroform andethanol in a ratio of 6:1 by volume.

10.4 g1-phenyl-4-(γ-[4-(o-methoxyphenyl)-piperazinyl-(1)]-propylamino)-uracil,corresponding to a yield of 80%, were obtained. The substance,recrystallized from ethanol, had a melting point of 186°C.

EXAMPLE 303-Phenyl-4-(γ-[4-(o-methoxyphenyl)-piperazinyl-(1)]-propylamino-uraci

A mixture of 11.2 g (0.05 mole) 3-phenyl-4-chlorouracil and 27.5 g (0.11mole) N-(o-methoxyphenyl)-N'-(γ-aminopropyl)-piperazine was heated for 1hour at 160°C. The reaction mixture was cooled and dissolved in about200 ml chloroform and about 200 ml water. The organic phase wasseparated and the solvent evaporated. The residue was worked upchromatographically in a column of silica gel "neutral" (Merck A.G.)having a particle size of 0.05 to 0.2 mm. The flow agent used was amixture of chloroform and ethanol in a ratio of 6:1 by volume. 4 g of3-phenyl-4-(γ-[4-(o-methoxyphenyl)-piperazinyl-(1)]-propylamino)-uracilwere obtained as the fastest passing substance, representing a yield of18%. The substance was recrystallized from ethanol and had a meltingpoint of 218°C.

EXAMPLE 311,3-Dimethyl-4-(γ-[4-(o-methoxyphenyl)-piperazinyl-(1)]-propylamino-5-diethylamino-uracil

To a solution of 10 g (0.026 mole)1,3-dimethyl-4-(γ-[4-(o-methoxyphenyl)-piperazinyl-(1)]-propylamino-uracil(see Example 4) in 60 ml chloroform was added drop by drop at 0°C andwithin 2 hours a solution of 4.5 g (0.028 mole) bromine in 28 mlchloroform. The reaction mixture was permitted to sit overnight at roomtemperature, whereafter 20 ml diethylamine were added, followed byboiling under reflux for 2 hours. The cooled mixture was then extractedwith water, the remaining organic phase was dried and the solventevaporated. The residue was purified chromatographically in a column ofsilica gel "neutral" (Merck A.G.) of a particle size of 0.05 to 0.02 mm.The flow agent was a mixture of chloroform and methanol in a ratio of40:1 by volume. In this manner, 5.5 g1,3-dimethyl-4-(γ-[4-(o-methoxyphenyl)-piperzainyl-(1)]-propylamino)-5-diethylamino-uracilwere obtained as a light yellow oil, representing a yield of 46%. Thetrihydrochloride of this compound was obtained with one mole ofcrystallization and had a melting point of 231°C.

EXAMPLE 321,3-Dimethyl-4-(γ-[4-(o-methoxyphenyl)-piperazinyl-(1)]-propylamino)-uracil-5-carbonicacid anilide

3.6 g (0.03 mole) phenylisocyanate were added drop by drop at roomtemperature to the suspension of 10 g (0.026 mole)1,3-dimethyl-4-(γ-[4-(o-methoxyphenyl)-piperazinyl-(1)]-propylamino)-uracil(see Example 4) in 100 ml toluene and subsequently boiled under refluxfor 9 hours. The solvent was then distilled off and the residue boiledout with ethanol for purification. 10.8 g1,3-dimethyl-4-(γ-[4-(o-methoxyphenyl)-piperazinyl-(1)]-propylamino)-uracil-5-carbonicacid anilide were obtained as the undissolved residue, having a meltingpoint of 165°C and representing a yield of 81%.

EXAMPLE 331,3-Dimethyl-4-(γ-[4-(o-methoxyphenyl)-piperazinyl-(1)]-propylamino-5-acetyl-uracil

10 g (0.026 mole)1,3-dimethyl-4-(γ-[4-(o-methoxyphenyl)-piperazinyl-(1)]-propylamino-uracil(see Example 4) were heated with 30 ml acetic acid anhydride for 5 hoursat 50°-60°C. Thereafter, 70 ml ethanol were added to the brown solutionand the solvents were evaporated in vacuo. The addition of ether to theresidue resulted in crystallization of the starting material, which wasfiltered off. The ether was then distilled off from the filtrate and theresidue chromatographically purified in a column of silica gel "neutral"(Merck A.G.) of a particle size of 0.05-0.2 mm. The flow agent was amixture of ethyl acetate, methanol and concentrated aqueous ammonia in aratio of 20:4:1.

In this manner, 4.5 g of an oil were obtained, which had the abovestated composition and which represents a yield of 40%. The oil could becrystallized by the addition of ether. Recrystallized from cyclohexaneit had a melting point of 97°-98°C.

EXAMPLE 341,3-Dimethyl-4-[N-ethyl-N-(γ-[4-(o-methoxyphenyl)-piperazinyl-(1)]-propyl)-amino]-uracil

A mixture of 3.5 g (0.02 mole) of 1,3-dimethyl-4-chlorouracil and 9 g(0.032 mole) N-(o-methoxyphenyl-N'-(γ-ethylaminopropyl)-piperazine washeated for 1/2 hour at 120°C. The reaction product was subject to columnchromatographic separation, resulting in 5 g of an oil having the abovestated composition and representing 75% yield calculated as the reactedquantity of the starting materials. The oil was converted into thedihydrochloride of the base by contacting it with a solution of HCl inethanol. The dihydrochloride compound was then recrystallized fromisopropanol and found to decompose at a temperature beginning at 162°C.

EXAMPLE 351,3-Dimethyl-4-(1-methyl-2-[4-(o-methoxyphenyl)-piperazinyl-(1)]-ethyloxy-uracil-dihydrochloride

2.5 g (0.1 mole) N-(o-methoxyphenyl)-N'-(2-hydroxypropyl)-piperazine in150 ml absolute toluene were boiled under reflux for 0.5-1 hour with 5.3g (0.12 mole) of a 55% sodium hydride suspension in oil. To the cooledreaction mixture were added 19.2 g (0.11 mole)1,3-dimethyl-4-chloro-uracil with subsequent boiling under reflux for0.5-1 hour. The reaction product was cooled and washed with water and,after separation, the toluene was evaporated from the toluene solution.The residue was dissolved in 300 ml acetone and the dihydrochloride ofthe desired compound was precipitated by the addition of ethanolsaturated with HCl.

36 g1,3-dimethyl-4-(1-methyl-2-[4-(o-methoxyphenyl)-piperazinyl-(1)]-ethyloxy)-uracil-dihydrochloridehaving a melting point of 220°C, were obtained representing a yield of78%.

EXAMPLE 361,3-Dimethyl-4-(1-methyl-2-[4-phenyl-piperazinyl-(1)]-ethoxy)-uracil-dihydrochloride

Using N-phenyl-N'-(2-hydroxypropyl)-piperazine as the starting materialthe method of Example 35 produced1,3-dimethyl-4-(1-methyl-2-[4-phenyl-piperazinyl-(1)]-ethoxy)-uracil inform of an oil in a yield of 49%. The oil was converted by contact withHCl into the corresponding dihydrochloride, which sintered at 170°C.

EXAMPLE 371,3-Dimethyl-4-(1-methyl-2-[4-(p-methylphenyl)-piperazinyl-(1)]-ethoxy)-uracil

Using N-(p-methylphenyl)-N'-(2-hydroxypropyl)-piperazine as the startingmaterial in the method of Example 35,1,3-dimethyl-4-(1-methyl-2-[4-(p-methylphenyl)-piperazinyl-(1)]-ethoxy-uracilwas obtained in a yield of 70%. The substance had a melting point of120°C.

EXAMPLE 381,3-Dimethyl-4-(1-methyl-2-[4-(p-chlorophenyl)-piperazinyl-(1)]-ethyloxy)-uracil

Using in the method of Example 35N-(p-chlorophenyl)-N'-(2-hydroxypropyl)-piperazine as the startingmaterial,1,3-dimethyl-4-(1-methyl-2-[4-(p-chlorophenyl)-piperazinyl-(1)]-ethyloxy)-uracil,having a melting point of 163°C, was obtained in a yield of 80%.

EXAMPLE 391,3-Dimethyl-4-(1-methyl-2-[4-(o-methoxyphenyl)-piperazinyl-(1)]-ethylthio)-uracil

A mixture of 33.5 g (0.15 mole) o-methoxyphenyl-piperazine carbonate and22 g (0.3 mole) propylenesulfide was boiled under reflux for 1 hour in100 ml methanol. Excess propylenesulfide was subsequently removed invacuo. The residue was dissolved in a solution of 5.6 g (0.1 mole)potassium hydroxide in 100 ml methanol and the methanol evaporated invacuo. By treating the dry residue with acetone at room temperature, thehygroscopic potassium salt of the mercapto compound was isolated.

9.5 g (0.31 mole) of this mercapto compound were heated on the steambath for 2 hours with 5 g (0.028 mole) of 1,3-dimethyl-4-chlorouracil.Of the two phases, the heavier one solidified upon cooling. The aqueoussolution was decanted and the residue was twice recrystallized frommethanol. In this manner 9.8 g1,3-dimethyl-4-(1-methyl-2-[4-(o-methoxyphenyl)-piperazinyl-(1)]-ethylthio)-uracil,having a melting point of 148°C, were obtained, representing a yield of78% calculated on the basis of the 1,3-dimethyl-4-chlorouracil startingmaterial.

EXAMPLE 401,3-Dimethyl-4-(1-methyl-2-[4-(o-methoxyphenyl)-piperazinyl-(1)]-ethylthio)-uracil

Using in the method of Example 39 phenylpiperazine carbonate as thestarting material,1,3-dimethyl-40(1-methyl-2-[4-phenyl-piperazinyl-(1)]-ethylthio)-uracilwas obtained in a yield of 59%. The dihydrochloride of this compound hada melting point of 230°C.

EXAMPLE 411,3-Dimethyl-4-(1-methyl-2-[4-(m-tolyl)-piperazinyl-(1)]-ethylthio)-uracil-dihydrochloride

When m-tolylpiperazine carbonate was used as the starting material inthe method of Example 39,1,3-dimethyl-4-(1-methyl-2-[4-(m-tolyl)-piperazinyl-(1)]-ethylthio)-uracilwas obtained in a yield of 48%. The dihydrochloride of this compound hada melting point of 217°C.

EXAMPLE 421,3-Dimethyl-4-(1-methyl-2-[4-(p-tolyl)-piperazinyl-(1)]-ethylthio)-uracil

Using in the method of Example 39 p-tolyl-piperazine carbonate as thestarting material,1,3-dimethyl-4-(1-methyl-2-[4-(p-tolyl-piperazinyl-(1)]-ethylthio)-uracil,having a melting point of 152°C, was obtained in a yield of 45%.

EXAMPLE 431,3-Dimethyl-4-(1-methyl-2-[4-(p-chlorophenyl)-piperazinyl-(1)]-ethylthio)-uracil

Substituting in the method of Example 39 p-chlorophenyl-piperazinecarbonate as the starting material,1,3-dimethyl-4-(1-methyl-2-[4-(p-chlorophenyl-piperazinyl-(1)]-ethylthio)-uracil,having a melting point of 152°C, was obtained in a yield of 28%.

1,3-Dimethyl-4-(γ-chloropropylamino)-uracil, which was used as thestarting material in Examples 1, 2, 3, 4a, 4b, 5, 6, 7 and 8, may beproduced as follows:

210 g (1.2 mole) 1,3-dimethyl-4-chlorouracil were gradually added to 225g (3 moles) 3-aminopropanol at 100°C. After completion of the reaction,in which the temperature increased to 150°C, the reaction mixture wascooled to 110°C and 200 ml water were added, whereafter the mixture wascooled to 0°C. The precipitated crystalline material was filtered off bysuction and washed with ice water and thereafter with acetone and driedover night in a vacuum drying oven at 60°C. 228 g1,3-dimethyl-4-(γ-hydroxypropylamino)-uracil, having a melting point of140°-143°C, were obtained, representing a yield of 90%.

To the suspension of 180 g (0.85 mole)1,3-dimethyl-4-(γ-hydroxypropylamino)-uracil in 800 ml toluene wereadded dropwise with stirring 155 ml (2.55 moles) thionylchloride. Thereaction mixture was cooled sufficiently to prevent that the temperatureexceeded 50°C. When the violent evolution of gas subsided, the mixturewas gradually heated to 100°C, until the formation of gas came nearly toan end. Thereafter, excess thionylchloride was distilled off in vacuoand the precipitate was filtered off by suction and washed with benzene.The compound was recrystallized from methanol. 167 g1,3-dimethyl-4-(γ-chloro-propylamino)-uracil, having a melting point of151°-153°C were obtained, representing a yield of 85%.

1,3-Dimethyl-4-(γ-chloroethylamino)-uracil, which was used as thestarting material in Example 10, was produced in a manner similar tothat described above. Substituting in the foregoing method1,3-dimethyl-4-(γ-hydroxy-ethylamino)-uracil, which is described byGoldner and Carstens in Liebigs Annalen 691, 142 (1966), for the1,3-dimethyl-4-(γ-hydroxypropylamino)-uracil,1,3-dimethyl-4-(γ-chloroethylamino)-uracil, having a melting point of203°C, was obtained in a yield of 74%.

1,3-Dimethyl-4-(γ-chloroethylamino)-uracil was also produced by thefollowing method:

To an ice cooled suspension of 20 g (0.1 mole),1,3-dimethyl-4-(γhydroxyethylamino)-uracil in 300 ml chloroform and 16ml dimethylformamid was added dropwise a mixture of 16 mlthionylchloride and 40 ml chloroform. The reaction mixture was stirredfor two hours with cooling by ice and for an additional 10 hours at roomtemperature. To the dark red, clear solution thus obtained, was addedice water and sodium bicarbonate solution, and the organic chloroformphase separated from the aqueous phase. The chloroform phase was driedand the chloroform evaporated. The residue was recrystallized frommethanol. In this manner -- and with further recovery from the motherliquor -- 16.1 g 1,3-dimethyl-4-(γ-chloroethylamino)-uracil, having amelting point of about 203°C, were obtained, representing a yield of74%.

1,3-Dimethyl-4-chloro-5-nitro-uracil used in Example 16 as the startingmaterial is described in the Literature by Pfleiderer, Ber. 99, 2997(1966).

1,3-Dimethyl-4-(γ-bromo-propyloxy)-uracil used in Example 9a as thestarting material may be produced by the following method:

Equivalent amounts of 1,3-dimethyl barbituric acid and silver nitratewere mixed in form of their aqueous solutions to produce the silver saltof the 1,3-dimethyl barbituric acid, which precipitated practicallyquantitatively from the solution. 10.4 g (0.04 mole) of this silver saltwere added to 40 g (0.2 mole) 1,3-dibromo-propane in 200 ml benzene. Themixture was boiled for 90 minutes with reflux, cooled, filtered and thebenzene evaporated from the filtrate. The residue was purifiedchromatographically in a column of 350 g silica gel "neutral" (MerckA.G.) having a particle size of 0.05 to 0.2 mm. The flow agent was amixture of ethyl acetate, methanol and concentrated aqueous ammonia in aratio of 20:4:1 by volume.

5.4 g of 1,3-dimethyl-4-(γ-bromo-propyloxy)-uracil were obtained,representing a yield of 25%. The substance, after recrystallization fromethyl acetate had a melting point of 113°-115°C.

1,3,5-Trimethyl-4-chloro-uracil, which was used as the starting materialin Example 14, may be produced by the following method:

6.1 ml 89% phosphoric acid was added dropwise to 92 ml phosphorusoxychloride with stirring. When the formation of gas was terminated, 34g (0.2 mole) 1,3,5-trimethyl-barbituric acid were added to the reactionmixture, followed by boiling under reflux for 2 hours. Thereafter,excess phosphorus oxychloride was distilled off in vacuo. The residuewas poured onto ice, resulting in an increase of the temperature toabout 90°-100°C. The crystals, precipitating on cooling of the mixture,were filtered off by suction. The remainder of the product was recoveredfrom the filtrate by extraction with chloroform. After recrystallizationfrom water, 23 g 1,3,5-trimethyl-4-chloro-uracil, having a melting pointof 135°C, were obtained, representing a yield of 61%. Using in the justdescribed method 1,3-dimethyl-5-n-butyl-barbituric acid as the startingmaterial instead of the 1,3,5-trimethyl-barbituric acid,1,3-dimethyl-4-chloro-5-n-butyl-uracil was obtained in a yield of 45%.This substance had a melting point of 59°-60°C and was used as thestarting material in the method of Example 15.

1-n-Butyl-4-chloro-uracil which was used as the starting material in themethod of Example 25, may be produced in the following manner:

To a solution of 23 g (1 g-atom) sodium metal in 500 ml absolute ethanolwere added at room temperature 35 g (0.3 mole) butyl-urea and 48 g (0.3mole) malonic acid-diethylester. The alcohol was then distilled off inan oil bath held at 120°C and the residue maintained at this temperaturefor about 16 hours. The residue was then cooled and dissolved in about300 ml water, stirred with activated carbon and the solution filtered.The clear filtrate was acidified by the addition of concentratedhydrochloric acid to produce 38 g 1-butyl-barbituric acid, representinga yield of 68%. The substance had, after recrystallization from benzene,a melting point of 107°-108°C.

10 g (0.055 mole) 1-butyl-barbituric acid were boiled for 3 hours underreflux with 110 ml phosphorus oxychloride and 7.7 ml 89% phosphoricacid. The excess phorphorus oxychloride was then distilled off and icewater and chloroform were given to the residue. The chloroform phase wasseparated, dried and the chloroform evaporated. 8.2 g1-butyl-4-chloro-uracil were obtained, representing a yield of 73%. Thesubstance, recrystallized from benzene, had a melting point of187°-189°C.

1-Cyclohexyl-4-chloro-uracil, which was used as the starting material inExample 24, may be produced by the following method:

16 g (0.075 mole) 1-cyclohexyl-barbituric acid were stirred for 16 hoursat 70°C with 150 ml phosphorus oxychloride and 10.5 ml 89% phosphoricacid. Thereafter, the excess phosphorus oxychloride was distilled off at70°C in vacuo. To the cooled residue was given, with stirring, ice waterand chloroform, the chloroform phase was separated and the chloroformevaporated. The residue was chromatographically purified in a stationarycolumn of silica gel "neutral" (Merck A.G.) having a particle size of0.02 to 0.5 mm. The flow agent was a mixture of chloroform and ether ina ratio of 6:1 by volume. 12 g 1-cyclohexyl-4-chloro-uracil wereobtained, representing a yield of 70%. After recrystallization fromethanol, the substance had a melting point of 222°-224°C.

1-Phenyl-4-chloro-uracil and 3-phenyl-4-chloro-uracil, which were usedas the starting materials in Examples 29 and 30, respectively, may beproduced by the following method:

41.0 g (0.02 mole) 1-phenyl-barbituric acid were boiled for 3 hoursunder reflux with 400 ml phosphorus oxychloride and 28 ml 89% phosphoricacid. The excess phosphorus oxychloride was then removed in vacuo andthe residue was treated with 1 liter ice water. The crystallineprecipitate was thereafter filtered off by suction and washed withwater, the filter residue was dissolved in 1 liter saturated sodiumbicarbonate solution and 1 liter chloroform with subsequent separationof the phases into a chloroform phase and an aqueous phase. Thechloroform was evaporated from the chloroform phase, the residueconsisted of 11.8 g 3-phenyl-4-chloro-uracil, representing a yield of26%. Recrystallized from ethanol, the substance had a melting point of256°C. To the aqueous phase were added 1.5 liter chloroform and 150 mlmethanol. The mixture was acidified by the addition of sufficient 2 nhydrochloric acid. In this manner, 13.8 g 1-phenyl-4-chloro-uracil wereextracted and recovered, representing a yield of 31%. Recrystallizationfrom ethanol resulted in a substance having a melting point of 265°C.

The starting materials used in Examples 35 to 38 may be produced inknown manner by boiling of the correspondingly substitutedphenylpiperazines with propyleneoxide in methanol, removal of thevolatile reactants and solvents in vacuo and recrystallization of theresidue. The reaction mechanism is as follows:Starting materialofExample No. Z Melting pontYield__________________________________________________________________________35o-OCH₃ 66°C 95%36 H 72-74°C 98%37 p-CH₃ 117-119°C 97%38 p-Cl 134-136°C55%__________________________________________________________________________

EXAMPLE 611,3-Dimethyl-4-([4-(o-tolyl)-piperazinyl-(1)]-propylamino)-5-nitroso-uracil

The nitroso substituent is introduced into1,3dimethyl-4-(-[4-(o-tolyl)-piperazinyl-(1)]-propylamino)-5nitroso-uracil(obtained in example 12) by adding drop-wise 10 ml of a 18% methanolichydrochloric acid soluton to 3.7 g. (0.01 mole) of the starting uraciland 3 ml of i-amylnitrite in 20 ml of chloroform and 10 ml of acetone.When a nearly white final precipitate is formed, after the color of thesolution changed from light yellow to red and a precipitate was formed,the addition is stopped. The precipitate is separated by suction. Theresidue is washed with some acetone and ether. The product (5g) isobtained in 97% yield (of theory); its M.P. is 142°-145°C, withdecomposition.

EXAMPLE 62 1,3-Dimethyl-[4-(gamma-(o-methoxyphenyl)-piperazinyl-(1)]propylamino)-uracil

There are heated 250 g (1 mole) ofN-orthomethoxyphenyl)-N'-(gamma-aminopropyl)-piperazine in 750 ml ofwater to 90°-100° C and there is added while stirring dropwise 88 g (0.5mole) of 1,3-dimethyl-4-chloruracil. Thereafter, there is added at90°-100° C as a single portion, a further 91 g (0.52 mole) of1,3-dimethyl-4-chloruracil.

After stirring for about an additional 10 minutes at 90°-100° C, thereis added portion-wise 88 g (1.05 mole) of solid sodium bicarbonate,whereupon active foaming takes place initially. When the addition isterminated stirring is continued for about 10-15 minutes at 90°-100° Cto promote the completeness of the reaction.

1,3-Dimethyl-[4-(gamma-(o-methoxyphenyl)-piperazinyl(1)]-Propylamino)-uraciloccurs then as an oil-like consistency, as the half-ester. There is thenslowly added to the hot reaction mixture enough ethanol (about 0.4 to0.5 liter) until a clear solution is obtained. The ethanol refluxes. Theclear solution can be sucked off hot. It is allowed to cool slowly,while stirring to 20°-20° C. The solution is seeded with somecrystalline1,3-dimethyl-4[4-(gamma(o-methoxyphenyl)-piperazinyl-)1)]-propylamino)-uracil.To promote the completeness of the crystallization there is addeddrop-wise about 1.2 liter water over 1 hour, about 20 minutes afterseeding. After about 30 minutes complete precipitation has occurred, theliquid is sucked off, and the precipitate is washed with 0.6 to 0.8liter of water.

Since the compound is readily soluble in aqueous acetone, theprecipitate is completely and carefully dried (until essentially free ofwater) at 70°-80°C under vacuum. Then, it is purified by boiling with500 ml of acetone, while stirring for 30 minutes, then allowed to cooland separated by suction, then washed with 300 ml of acetone and dried.The yield is 300 to 320 g (about 80% of theory); M.P. 155°-157°C.

The above described procedure represents a highly favored method forpreparing one of the most desirable uracils of the invention.

Water which was described herein above to be useful as a suitablesolvent in the reaction, is suitable in those instances (but notexclusively in those instances) in embodiment a) of the process whereinin formula II, R³ is hydrogen, methyl or ethyl and X is amino; inembodiment b) of the process wherein formula IV, R³ is hydrogen, methylor ethyl and formula V, X is amino.

The novel compounds of the invention and their pharmacologicallyacceptable salts with suitable inorganic or organic acids are usefulchemicals which have biological properties on mammalians and hence areuseful in therapy on humans.

The compounds of the invention lower the blood pressure, reduce theheart beat rate, inhibit and carotid sinus relaxation reflex, and blockthe blood pressure increasing effect of adrenaline and noradrenaline,intravenously administered to the despinalized rat. They have a sedativeand analgesic effect and also effective antihistaminics.

The compounds of the invention, as defined generically above are usefulfor the purposes described as shown hereinafter for the representativepiperazinyl-uracils.

The following Table II shows the effect of representative piperazinyluracils of the invention on the blood pressure, heart rate and thecarotid sinus relaxation reflex of the narcotized cat as compared withthe effect of phentolamine.

                                      Table II                                    __________________________________________________________________________    Effect of the aryl-substituted piperazinyl uracils of the invention on        the                                                                           blood pressure, heart rate and carotid sinus relaxation reflex of the         narcotized cat.                                                                       Lowering of the        Inhibiton of the carotid                       Compound of                                                                           blood pressure by                                                                         Heart rate sinus reflex by                                        30% with                                                                            50% with         30% with                                                                            50% with                                 Example No.                                                                           mg/kg i.v.                                                                          mg/kg i.v.                                                                          lowered                                                                            increased                                                                           mg/kg i.v.                                                                          mg/kg i.v.                               __________________________________________________________________________     4      0.14  0.65  +    -     0.03  0.16                                      9      0.03  0.14  -    -     0.17  0.26                                     12      0.41  2.4   +    -                                                    16      0.21  1.0   -    -     0.60  2.0                                      18      0.15  >0.5  -    -     0.13  1.1                                      20      0.05  0.15  -    -     0.06  0.15                                     Phentol-                                                                      amin    0.1   0.7   -    +     0.1   0.5                                      __________________________________________________________________________

Table III shows the effect of representative piperazinyl uracils of theinvention on the blood pressure and on the heart beat rate of thenarcotized rat and the influence on the blood pressure increasing effectof 0.001 mg/kg i.v. of adrenaline and noradrenaline on the despinalizedrat, as compared to the corresponding effects of phentolamine.

                                      Table III                                   __________________________________________________________________________                                          Despinalized rat                                                              50% inhibiton of the press.                                                   effect after i.v. adminis-                                Rat narcotized      tration of                                      LD.sub.50 lowering of the                                                                        heart rate adrenaline                                                                           noradrenaline                    Compound of                                                                           (median lethal                                                                          blood pressure      with   with                             Example No.                                                                           dose) in the mouse                                                                      by 30% by                                                                              lowered                                                                            increased                                                                           mg/kg i.v.                                                                           mg/kg i.v.                       __________________________________________________________________________     1      200       2.9      -    -     1.45   --                                3      430       1.4      +    -     2.1    --                                4      400       0.71     +    -     0.36   1.9                               5      250       0.36     +    -     0.24   --                                9      400       >3.4     -    -     0.15   --                               11      120       0.48     +    -     1.0    >2.5                             12       70       1.0      +    -     0.45   2.5                              13       70       >3.4     +    -     >2.5   --                               14      140       0.13     +    -     0.045  1.2                              15      130       0.36     +    -     0.028  2.8                              16      600       1.6      -    +     0.17   --                               17      220       3.0      -    +     0.16   113 2.3                          20      500       0.11     +    -     0.045  1.6                              61      600       0.5      +    -     0.39   3.7                              Phentol-                                                                      amin    200       0.63     -    +     0.047   0.18                            __________________________________________________________________________

Phentolamine,2-[N'-p-tolyl-N'-(m-hydroxyphenyl)aminomethyl]-2-imidiozoline is arecognized vasodepressor agent specifically inhibiting the stimulatingeffect of adrenaline and noradrenaline, typical alpha-blocking agent.

Tables II and III show that the typical piperazinyl uracils of theinvention have a more pronounced lowering effect on the blood pressureand at the same time a lower toxicity than phentolamine. The inhibitionof the carotid sinus reflex, caused by the piperazine uracils of theinvention takes place at lower doses than the spontaneous lowering ofthe blood pressure in the cat. This is evidence that the compounds ofthe invention inhibit the central blood pressure increasing mechanism ofthe circulatory system.

Chlordiazepoxyde has been used for a variety of conditions involvinganxiety, as a sedative and as hypnotic, also as a sedative. Meprobatelikewise has been used for such uses. The compounds of the inventionlikewise exhibit such properties.

The centrally inhibiting effect of the piperazinyl uracils of theinvention in the mouse are apparent from Table IV. A comparison betweenthe doses which affect the circulation and those which are centrallyinhibiting shows that the effect on the blood circulatory system takeplace preferentially. The selective action of the compounds of theinvention on the central blood pressure mechanism can be usedadvantageously in human therapy in the treatment of hypertonic diseases.The compounds of the invention represent a new type of antihypertensivepharmaceuticals which is not comparable in its mechanism withconventional available hypertonics.

                                      Table IV                                    __________________________________________________________________________    Central effects in the mouse                                                          a   b   c              d                                                      PD.sub.50                                                                         SD.sub.50                                                                         % Inhibition of the motility                                                                 % prolongation of                                              in the tread wheel by                                                                        sleep induced by                               Compound of                                                                           mg/kg                                                                             mg/kg                                                                             12 mg/kg                                                                              25 mg/kg                                                                             hexobarbital by                                Example No.                                                                           i.p.                                                                              oral                                                                              i.p.    i.p.   15 mg/kg i.p.                                  __________________________________________________________________________     1      28  40  -       36     110                                             4      52  100 -       36     71                                              5      26  98  -       46     126                                             9      12  30  -       79     140                                            11      11  70  22       -     130                                            12      26  87  42       -     49                                             14      12  90  -       21     152                                            20      34  80  -       42     62                                             Chlordiazep-                                                                  oxyde   38   8  -       30     324                                            Meprobamate                                                                           95  300 -       +28    18                                             __________________________________________________________________________

Explanation of Table IV.

a = Dose, at which an average of 50% of the mice fall from a rotatingrod.

b = Dose, at which at an average 50% of the mice show the followingsymptoms: inhibition of the spontaneous motility, sadation, musclerelaxation, loss of gripping and holding ability on a horizontal wirenet.

c = average inhibition of the running activity in percent of mice, towhich was administered 5 mg/kg d-amphetamine-sulfate (compared withmice, which were administered d-amphetaminesulfate only) during 180minutes.

d = Percent prolongation of the duration of sleep of mice, which wereadministered 75 mg/kg hexobarbital, compared with the sleep duration ofcontrols.

Aminopyrine (aminophenazone, pyramidone) have been used for analgesiaand for their anti-inflammatory effects.

Tables V and VI demonstrated the analgesic effect and the antihistamineeffect of the piperazinyl uracils of the invention as compared with theeffects of aminophenazone and piprinhydrinate, respectively. Theanalgesic effect was thereby determined as the delay in the reactionupon thermal stimulation of the tail of the mouse.

                  Table V                                                         ______________________________________                                                      Analgesic effect in the mouse                                                 Retardation of the defense reaction                             Compound of   upon thermal stimulation of the                                               tail of the mouse by 25%                                        Example No.   by mg/kg orally administered                                    ______________________________________                                        1             5.0                                                             3             7.0                                                             4             2.4                                                             5             9.0                                                             9             10.0                                                            12            6.5                                                             16            10.0                                                            Aminophenazone                                                                              140.0                                                           ______________________________________                                    

                  Table VI                                                        ______________________________________                                                         Antihistamine effect                                                          50% inhibition of the hist-                                                   amine spasm of the isolated                                  Compound of      small intestine of the guinea                                                 pig by                                                       Example No.      g/ml                                                         ______________________________________                                         7                 2 × 10.sup.-.sup.8                                   12                 3 × 10.sup.-.sup.8                                   13                 1 × 10.sup.-.sup.8                                   Piprinhydrinate   1.5 × 10.sup.-.sup.8                                  ______________________________________                                    

For additional details regarding the above-described and otherapplications, reference is made to The Pharmacological Basis ofTherapeutics (3rd Ed.), Goodman & Gilman, The Macmillan Company, NewYork, 1968, especially Section II, chapter 17, Section V, chapter 20,Section VI, chapter 34.

Clinical tests were conducted with the1,3-dimethyl-4-(γ-[4-(o-methoxyphenyl)-piperazinyl-(1)]-propylamino)-uracilon two female and three male patients, with doses of 10, 20, 40 and 60mg orally administered. The compound was found to have excellentcompatibility, caused no adverse effect on perception and other sensoryfunctions and produced a statistically significant lowering of thesystolic and diastolic blood pressure.

Attached Diagrams 1 and 2 show the changes of the blood pressure underthe effect of various doses of1,3-dimethyl-4-(γ-[4-(o-methoxyphenyl)-piperazinyl-(1)]-propylamino)-uracil.Diagram 1 shows the changes of the systolic blood pressure under theeffect of doses from 0 to 60 mg of the uracil compound in a patienthaving an average systolic blood pressure (RR_(s)) of 171.9 mm Hg.Diagram 2 shows the changes of the diastolic blood pressure with thesame doses of the uracil compound at an average starting diastolic bloodpressure (RR_(d)) of 95.3 mm Hg plotted against the dose of the uracilcompound. These diagrams show clearly, that the blood pressure isprogressively lowered in response to an increasing dose of the uracilcompound. The difference in the effect of a dose of 20 mg and a dose of40 mg was statistically confirmed.

The pharmacological and clinical tests show, that piperazinyl uracils ofthe invention and their pharmacologically acceptable salts withpharmacologically acceptable acids are valuable medicaments, especiallyfor the treatment of hypertonicity.

The invention is therefore also concerned with medicaments or drugs,which are characterized by comprising one or more of the compounds ofthe invention or of the pharmacologically acceptable salts thereof, incombination with a pharmaceutical acceptable carrier material and, ifdesired, with the usual auxiliary additives.

Standard modes of administration are contemplated. The new medicamentsmay, for instance, be formulated as dragees, tablets, capsules,suppositories, solutions for injection, or as syrup. The single dose is,in the case of oral administration, generally in the range from 5 to 100mg, preferably 20 to 60 mg of the effective piperazinyl uracil compound;in the case of intramuscular administration the single dose is generallyfrom 1 to 50 mg, preferably from 10 to 20 mg of the piperazinyl uracilsubstance.

In the case of intravenous administration the single dose is generallyfrom 1 to 30 mg, preferably from 5 to 15 mg of the piperazinyl uracilsubstance. The single doses of this magnitude may be adminstered severaltimes per day. Oral adminstration is preferred.

The following are two illustrations of the composition of dragees andinjection solution in ampules in accordance with the present invention.

    ______________________________________                                        Dragees                                                                       ______________________________________                                        Components:                                                                   1350.0 g 1,3-dimethyl-4-(γ-[4-(o-methoxypheny)-piperazinyl- -           (1)]-propylamino)-uracil                                                      1125.0 g corn starch                                                          1372.5 g lactose                                                               22.5 g "Aerosil"                                                              22.5 g gelatin                                                               135.0 g talc                                                                   22.5 g magnesium stearate                                                    ______________________________________                                    

The uracil substance, the corn starch, the lactose and the "Aerosil" aremixed. The mixture is sifted and granulated, together with the gelatineand 750 ml water through a sieve of 1.5 mm mesh size. After drying at40° C, the talc and the magnesium stearate are added and mixed in. Themixture is then pressed to dragee centers of 8 mm diameter and 180 mgweight. The dragee centers are then coated by the use of a rapid coatingsuspension of conventional composition to a weight of 220 mg. Eachdragee contains 60 mg of the effective uracil compound.

    ______________________________________                                        Ampules                                                                       ______________________________________                                        Components                                                                     10.0 g 1,3-dimethyl-4-(-[4-(o-methoxyphenyl)-piperazinyl-                      (1)]-propylamino)-uracil                                                    240.0 ml o.l n hydrochloric acid, aqueous                                      7.5 g sodium chloride                                                        filled up with water to 1000 ml.                                              ______________________________________                                    

The uracil compound is suspended in 500 ml water, the hydrochloric acidadded thereto and the mixture stirred to dissolve the uracil compound.To the solution there is added the sodium chloride, and water to makeone liter. The solution is filtered through a finely porous membranefilter layer ("Seitz 1121") and the filtrate filled into colorless 1 mlglass ampules, which are subsequently sterilized for 1 hour at 100° C.The injection solution made in this manner has a p_(H) of 6.0. It isuseful in cardiovascular therapy.

The compounds of the invention wherein Z is linked in the ortho positionlike o-alkoxy, or o-alkyl or where Z is hydrogen have especiallyenhanced effect on the blood circulatory system and as sedatives oranalgesics, whereas those compounds wherein Z is in the para positionare especially noteworthy for their antihistaminic effect.

We claim:
 1. A compound of Formula I ##SPC15##wherein R¹ and R² each ishydrogen, alkyl of 1 to 4 carbon atoms, cycloalkyl of 5 to 6 carbonatoms, and phenyl; R³ is hydrogen, alkyl of 1 to 4 carbon atoms,chlorine or bromine, nitro, nitroso, amino, alkylamino of 1 to 3 carbonatoms, dialkylamino wherein each of the alkyl groups contain 1 to 3carbon atoms, alkanoylamino of 1 to 4 carbon atoms, formyl,ethoxycarbonylamino, thiocyanato, COCH₃ or CONHC₆ H₅ ; X is -NH-, -NC₂H₅ -, -O- or -S-; A is -CH₂ -CH₂ -CH₂ -, -CH(CH₃)-CH₂ - or -CH₂-CH(CH₃); Z is hydrogen, a methyl group, one or two methoxy groups or anethoxy group, a chlorine atom and Y is hydrogen, and thepharmaceutically acceptable salts of these compounds.
 2. The compound ofclaim 1, wherein R³ is hydrogen, alkyl of 1 to 4 carbon atoms, bromine,amino and diethylamino, and wherein Z is methoxy.
 3. The salt of thecompound of claim 1 with an acid of the group consisting of acetic acid,oxalic acid, maleic acid, fumaric acid, tartaric acid, benzoic acid,pamoic acid, salicylic acid, polygalacturonic acid, polyvinylcarboxylicacid, hydrochloric acid, sulfuric acid, phosphoric acid, amidosulfonicacid and methanesulfonic acid.
 4. The compound of claim 1, wherein atleast one of R¹ and R² is methyl.
 5. The compound of claim 1, wherein R³is hydrogen, alkyl of 1 to 4 carbon atoms, amino or diethylamino.
 6. Thecompound of claim 1, wherein Z is methoxy in the o-position.
 7. Thecompound of claim 1, wherein R³ is bromine, amino or diethylamino. 8.The compound of claim 1, wherein R¹ is methyl.
 9. The compound of claim1, wherein R³ is hydrogen.
 10. The compound of claim 1, wherein X is-NH-.
 11. The compound of claim 1, wherein R² is methyl.
 12. Thecompound of claim 1, wherein R¹ and R² both are methyl.
 13. The compoundof claim 1, wherein R³ is --CH₃, n--C₄ H₉, --NO₂, --Br, --Cl, --NO,--NH₂, -NHCOC₂ H₅, -CH=O, -NHCOOC₂ H₅, or -SCN.
 14. The compound ofclaim 1, wherein R¹ is methyl. R² is methyl, R³ is hydrogen, X is--NH--, A is --CH₂ --CH₂ --CH₂ --, Y is hydrogen and Z is p--CH₃, o--Cl,2,5-dimethoxy, o--CH₃, o--CH₂ H₅, 2,4-dimethoxy, o-methoxy, m-methoxy,p-methoxy, hydrogen, or p--Cl.
 15. The compound of claim 1, wherein R¹is --CH₃, R² is --CH₃, R³ is hydrogen, X is --O--, A is --CH(CH₃)--CH₂--, Y is hydrogen and Z is hydrogen, p--Cl or p--CH₃.
 16. The compoundof claim 1, wherein R¹ is --CH₃, R² is --CH₃, R³ is hydrogen, X is--S--, A is --CH(CH₃)--CH₂ --, Y is hydrogen and Z is o--OCH₃, hydrogen,m--CH₃, p--CH₃ or p--Cl.
 17. The compound of claim 1, wherein R¹ is--CH₃, R² is --CH₃ , R³ is hydrogen, X is --NH--, Y is hydrogen, Z iso--OCH₃ and A is --CH₂ --CH(CH₃)--, --CH(CH₃)--CH₂ -- or --CH₂ --CH₂--CH₂.
 18. The compound of claim 1, wherein R¹ is --CH₃, R² is hydrogen,R³ is hydrogen, A is --CH₂ --CH₂ --CH₂ --, Y is hydrogen, Z is o--OCH₃and X is --NH--, --N(C₂ H₅)-- or --O--.
 19. The compound of claim 1,wherein R² is hydrogen, R³ is hydrogen, X is --NH--, A is --CH₂ --CH₂--CH₂ --, Y is hydrogen, Z is o--OCH₃ and R¹ is hydrogen, butyl,cyclohexyl and phenyl.
 20. The compound of claim 1 of the groupconsisting of1,3-dimethyl-4-(γ-[4-(o-methoxyphenyl)-piperazinyl-(1)]-propylamino-uraciland a salt of this compound with a pharmaceutically acceptable acid. 21.The salt of claim 1, which is1,3-dimethyl-4-(γ[4-(o-methoxyphenyl)-piperazinyl-(1)]-propylamino-5-bromo-uracil-dihydrobromide.22. The compound of claim 1 wherein R₃ is NO₂.
 23. The compound of claim1 wherein R₃ is Br.
 24. The compound of claim 1 wherein R₃ is NH₂. 25.The compound of claim 1 wherein R₃ is SCN. 26.1,3-Dimethyl-4-(gamma-[4-(o-methoxyphenyl)piperazinyl-(1)]-propylamino)-5-propionylamino-uracil.27.1,3-Dimethyl-4-(1-methyl-2[4(orthomethoxyphenyl-piperazinyl(1)]-ethyloxyuracil-dihydrochloride.
 28. The compound of claim 1 wherein thealkanoylamino of R³ is propionyl amino.
 29. The compound of claim 1wherein R₃ is hydrogen, CH₃, n-C₄ H₉, NO₂, Br, NO, NH₂, NH(CO₂ C₂ H₅),NHCO-C₂ H₅, CHO, SCN, N(C₂ H₅), CONHC₆ H₅ or COCH₃.